Genetic code
molecule. Each codon consists of three nucleotides, representing a single amino acid.]] The genetic code is the set of rules by which information encoded in genetic material (DNA or RNA sequences) is translated into proteins (amino acid sequences) by living cells. Specifically, the code defines a mapping between tri-nucleotide sequences called codons and amino acids; every triplet of nucleotides in a nucleic acid sequence specifies a single amino acid. Most organisms use a nearly universal code that is referred to as the standard genetic code. Even viruses, which are not cellular and do not synthesize proteins themselves, have proteins made using this standard code. For a time, therefore, the code was thought to be universal. However, there are notable exceptions. It is also possible for a single organism to translate different parts of the genome in different ways. For example, in humans, protein synthesis in mitochondria relies on a modified genetic code that varies from the standard one. Transfer of information via the genetic code The genetic information carried by an organism, its genome, is inscribed in one or more DNA, or in some cases RNA, molecules. Each functional portion of a DNA or RNA molecule is referred to as a gene. The gene sequence inscribed in DNA, and in RNA, is composed of tri-nucleotide units called codons, each coding for a single amino acid. Each nucleotide sub-unit consists of a phosphate, deoxyribose sugar and one of the 4 nitrogenous nucleotide bases grouped into 2 categories, purine and pyrimidine. The purine bases adenine (A') and guanine ('G) are larger and consist of two aromatic rings. The pyrimidine bases cytosine (C') and thymine ('T) are smaller and consist of only one aromatic ring. In RNA, however, thymine (T') is substituted by uracil ('U), and the deoxyribose is substituted by ribose. Each protein-coding gene is transcribed into a short template molecule of the related polymer RNA, known as messenger RNA or mRNA. This in turn is translated on the ribosome into an amino acid chain or polypeptide, which will then fold, resulting in secondary and tertiary structures. The process of translation requires transfer RNAs specific for individual amino acids with the amino acids covalently attached to them, guanosine triphosphate as an energy source, and a number of translation factors. tRNAs have anticodons complementary to the codons in mRNA and can be "charged" covalently with amino acids at their 3' terminal CCA ends. Individual tRNAs are charged with specific amino acids by enzymes known as aminoacyl tRNA synthetases which have high specificity for both their cognate amino acids and tRNAs. The high specificity of these enzymes is a major reasons why the fidelity of protein translation is maintained. Theoretically, there are 4³ = 64 different codon combinations possible with a triplet codon of three nucleotides. In reality, all 64 codons of the standard genetic code are assigned for either amino acids or stop signals during translation. If, for example, an RNA sequence, UUUAAACCC is considered and the reading-frame starts with the first U (by convention, 5' to 3'), there are three codons, namely, UUU, AAA and CCC, each of which specifies one amino acid. This RNA sequence will be translated into an amino acid sequence, three amino acids long. The standard genetic code is shown in the following tables. Table 1 shows what amino acid each of the 64 codons specifies. Table 2 shows what codons specify each of the 20 standard amino acids involved in translation. These are called forward and reverse codon tables, respectively. For example, the codon AAU represents the amino acid asparagine, and UGU and UGC represent cysteine {standard three-letter designations, Asn and Cys respectively). Table 1: RNA codon table This table shows the 64 codons and the amino acid each codon codes for. The direction is 5' to 3'. 2nd base U C A G 1st base U UUU (Phe/F)Phenylalanine UUC (Phe/F)Phenylalanine UUA (Leu/L)Leucine UUG (Leu/L)Leucine UCU (Ser/S)Serine UCC (Ser/S)Serine UCA (Ser/S)Serine UCG (Ser/S)Serine UAU (Tyr/Y)Tyrosine UAC (Tyr/Y)Tyrosine UAA Ochre (Stop) UAG Amber (Stop) UGU (Cys/C)Cysteine UGC (Cys/C)Cysteine UGA Opal (Stop) UGG (Trp/W)Tryptophan C CUU (Leu/L)Leucine CUC (Leu/L)Leucine CUA (Leu/L)Leucine CUG (Leu/L)Leucine CCU (Pro/P)Proline CCC (Pro/P)Proline CCA (Pro/P)Proline CCG (Pro/P)Proline CAU (His/H)Histidine CAC (His/H)Histidine CAA (Gln/Q)Glutamine CAG (Gln/Q)Glutamine CGU (Arg/R)Arginine CGC (Arg/R)Arginine CGA (Arg/R)Arginine CGG (Arg/R)Arginine A AUU (Ile/I)Isoleucine AUC (Ile/I)Isoleucine AUA (Ile/I)Isoleucine AUG (Met/M)Methionine, Start''The codon AUG both codes for methionine and serves as an initiation site: the first AUG in an mRNA's coding region is where translation into protein begins. ACU (Thr/T)Threonine ACC (Thr/T)Threonine ACA (Thr/T)Threonine ACG (Thr/T)Threonine AAU (Asn/N)Asparagine AAC (Asn/N)Asparagine AAA (Lys/K)Lysine AAG (Lys/K)Lysine AGU (Ser/S)Serine AGC (Ser/S)Serine AGA (Arg/R)Arginine AGG (Arg/R)Arginine G GUU (Val/V)Valine GUC (Val/V)Valine GUA (Val/V)Valine GUG (Val/V)Valine GCU (Ala/A)Alanine GCC (Ala/A)Alanine GCA (Ala/A)Alanine GCG (Ala/A)Alanine GAU (Asp/D)Aspartic acid GAC (Asp/D)Aspartic acid GAA (Glu/E)Glutamic acid GAG (Glu/E)Glutamic acid GGU (Gly/G)Glycine GGC (Gly/G)Glycine GGA (Gly/G)Glycine GGG (Gly/G)Glycine Table 2: Reverse codon table This table shows the 20 standard amino acids used in proteins, and the codons that code for each amino acid. Salient features Reading frame of a sequence Note that a codon is defined by the inital nucleotide from which translation starts. For example, the string GGGAAACCC, if read from the first position, contains the codons GGG, AAA and CCC;and if read from the second position, it contains the codons GGA and AAC; if read starting from the third position, GAA and ACC. Partial codons have been ignored in this example. Every sequence can thus be read in three 'reading frames, each of which will produce a different amino acid sequence (in the given example, Gly-Lys-Pro, Gly-Asp, or Glu-Thr, respectively). With double-stranded DNA there are six possible reading frames, three in the forward orientation on one strand and three reverse, or on the opposite strand. The actual frame a protein sequence is translated in is defined by a '''start codon, usually the first AUG codon in the mRNA sequence. Mutations that disrupt the reading frame by insertions or deletions of one or two nucleotide bases are known as frameshift mutations. These mutations may impair the function of the resulting protein, if it is formed, and are thus rare in in vivo protein-coding sequences. Often such misformed proteins are targeted for proteolytic degradation. One reason for the rareness of frame-shifted mutations being inherited is that if the protein being translated is essential for growth under the selective pressures the organism faces, absence of a functional protein may cause lethality before the organism is viable. Start/stop codons Translation starts with a chain initiation codon (start codon). Unlike stop codons, the codon alone is not sufficient to begin the process. Nearby sequences and initiation factors are also required to start translation. The most common start codon is AUG, which also codes for methionine, but other start codons are also used. The three stop codons have been given names: UAG is amber, UGA is opal (sometimes also called umber), and UAA is ochre. "Amber" was named after its discoverer Harris Bernstein, whose last name means "amber" in German. The other two stop codons were named 'ochre" and "opal" in order to keep the "color names" theme. Stop codons are also called termination codons and they signal release of the nascent polypeptide from the ribosome due to binding of release factors in the absence of cognate tRNAs with anticodons complementary to these stop signals.http://www.sci.sdsu.edu/~smaloy/MicrobialGenetics/topics/rev-sup/amber-name.html Degeneracy of the genetic code Many codons are redundant, meaning that two or more codons can code for the same amino acid. Degenerate codons may differ in their third positions; e.g., both GAA and GAG code for the amino acid glutamic acid. A codon is said to be four-fold degenerate if any nucleotide at its third position specifies the same amino acid; it is said to be two-fold degenerate if only two of four possible nucleotides at its third position specify the same amino acid. In two-fold degenerate codons, the equivalent third position nucleotides are always either two purines (A/G) or two pyrimidines (C/T). Only two amino acids are specified by a single codon; one of these is the amino-acid methionine, specified by the codon AUG, which also specifies the start of translation; the other is tryptophan, specified by the codon UGG. The degeneracy of the genetic code is what accounts for the existence of silent mutations. Degeneracy results because a triplet code designates 20 amino acids and a stop codon. Because there are four bases, triplet codons are required to produce at least 21 different codes. For example, if there were two bases per codon, then only 16 amino acids could be coded for (4²=16). Because at least 21 codes are required, then 4³ gives 64 possible codons, meaning that some degeneracy must exist. These properties of the genetic code make it more fault-tolerant for point mutations. For example, in theory, four-fold degenerate codons can tolerate any point mutation at the third position, although codon usage bias restricts this in practice in many organisms; two-fold degenerate codons can tolerate one out of the three possible point mutations at the third position. Since transition mutations (purine to purine or pyrimidine to pyrimidine mutations) are more likely than transversion (purine to pyrimidine or vice-versa) mutations, the equivalence of purines or that of pyrimidines at two-fold degenerate sites adds a further fault-tolerance. A practical consequence of redundancy is that some errors in the genetic code only cause a silent mutation or an error that would not affect the protein because the hydrophilicity or hydrophobicity is maintained by equivalent substitution of amino acids; for example, a codon of NUN (where N = any nucleotide) tends to code for hydrophobic amino acids. Even so, it is a single point mutation that causes a modified hemoglobin molecule in sickle-cell disease. The hydrophilic glutamate (Glu) is substituted by the hydrophobic valine (Val), which reduces the solubility of ß-globin. In this case, this mutation causes hemoglobin to form linear polymers linked by the hydrophobic interaction between the valine groups causing sickle-cell deformation of erythrocytes. Sickle-cell disease is generally not caused by a de novo mutation. Rather it is selected for in malarial regions (in a similar way to thalassemia), as heterozygous people have some resistance to the malarial Plasmodium parasite (heterozygote advantage). These variable codes for amino acids are allowed because of modified bases in the first base of the anticodon of the tRNA, and the base-pair formed is called a wobble base pair. The modified bases include inosine and the Non-Watson-Crick U-G basepair. Variations Numerous variations of the standard genetic code are found in mitochondria, which are energy-producing organelles that are found inside eukaryotic cells. Mycoplasma translate the codon UGA as tryptophan. Ciliate protozoa also have some variation in the genetic code: UAG and often UAA code for glutamine (a variant also found in some green algae), or UGA codes for cysteine. Another variant is found in some species of the yeast, Candida, where CUG codes for serine. In addition in some rare cases certain proteins may also use alternate initiation (start) codons. In certain proteins, non-standard amino acids are substituted for standard stop codons, depending upon associated signal sequences in the messenger RNA: UGA can code for selenocysteine and UAG can code for pyrrolysine as discussed in the relevant articles. A detailed description of variations in the genetic code can be found at the NCBI web site. However, there may be other non-standard interpretations that are not yet known. Sequencing of genomes may reveal unique genetic codes that allow the incorporation of other novel amino acids into proteins. Origin of the genetic code Despite the variations that exist, the genetic codes used by all known forms of life on Earth are very similar. Since there are many possible genetic codes that are thought to have similar utility to the one used by Earth life, the theory of evolution suggests that the genetic code was established very early in the history of life. One can ask the question: is the genetic code completely random, just one set of codon-amino acid correspondences that happened to establish itself and be "frozen in" early in evolution, although functionally any of the many other possible transcription tables would have done just as well? Already a cursory look at the table shows patterns that suggest that this is not the case. There are three themes running through the many theories that seek to explain the evolution of the genetic code (and hence the origin of these patterns).Knight, R.D.; Freeland S. J. and Landweber, L.F. (1999) The 3 Faces of the Genetic Code. Trends in the Biochemical Sciences 24(6), 241-247. One is illustrated by recent aptamer experiments which show that some amino acids have a selective chemical affinity for the base triplets that code for them.Knight, R.D. and Landweber, L.F. (1998). Rhyme or reason: RNA-arginine interactions and the genetic code. Chemistry & Biology 5'(9), R215-R220. PDF version of manuscript This suggests that the current, complex transcription mechanism involving tRNA and associated enzymes may be a later development, and that originally, protein sequences were directly templated on base sequences. Another is that the standard genetic code that we see today grew from a simpler, earlier code through a process of "biosynthetic expansion". Here the idea is that primordial life 'invented' new amino acids (e.g. as by-products of metabolism) and later back-incorporated some of these into the machinery of genetic coding. Although much circumstantial evidence has been found to indicate that originally the number of different amino acids used may have been considerably smaller than today,Brooks, Dawn J.; Fresco, Jacques R.; Lesk, Arthur M.; and Singh, Mona. (2002). Evolution of Amino Acid Frequencies in Proteins Over Deep Time: Inferred Order of Introduction of Amino Acids into the Genetic Code. ''Molecular Biology and Evolution '''19, 1645-1655. precise and detailed hypotheses about exactly which amino acids entered the code in exactly what order has proved far more controversial.Amirnovin R. (1997) An analysis of the metabolic theory of the origin of the genetic code. Journal of Molecular Evolution 44(5), 473-6.Ronneberg T.A.; Landweber L.F. and Freeland S.J. (2000) Testing a biosynthetic theory of the genetic code: Fact or artifact? Proceedings of the National Academy of Sciences, USA 97(25), 13690-13695. A third is that natural selection organized the codon assignments of the genetic code to minimize the effects of genetic errors (mutations).Freeland S.J.; Wu T. and Keulmann N. (2003) The Case for an Error Minimizing Genetic Code. Orig Life Evol Biosph. 33(4-5), 457-77. References See also * Anticodon * Protein biosynthesis * Operon * lac operon Further reading * Griffiths, Anthony J.F.; Miller, Jeffrey H.; Suzuki, David T.; Lewontin, Richard C.; Gelbart, William M. (1999). [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=iga.TOC Introduction to Genetic Analysis (7th ed.)]. New York: W. H. Freeman & Co. ISBN 0-7167-3771-X * Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter. (2002). [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=mboc4.TOC&depth=2 Molecular Biology of the Cell (4th ed.)]. New York: Garland Publishing. ISBN 0-8153-3218-1 * Lodish, Harvey; Berk, Arnold; Zipursky, S. Lawrence; Matsudaira, Paul; Baltimore, David; Darnell, James E. (1999). [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=mcb.TOC Molecular Cell Biology (4th ed.)]. New York: W. H. Freeman & Co. ISBN 0-7167-3706-X External links * Online DNA → Amino Acid Converter * DNA Sequence → Protein Sequence converter * DNA to protein translation (6 frames/13 genetic codes) * Evolving Code - a themed wiki devoted to the topic of how the genetic code evolved, and its effects on the subsequent evolution of the genome: Category:Molecular genetics Category:Gene expression Category:Protein biosynthesis bg:Генетичен код ca:Codi genètic cs:Genetický kód da:Genetisk kode de:Genetischer Code et:Geneetiline kood es:Codón eo:Genetika Kodo fr:Code génétique ko:코돈 it:Codice genetico he:הקוד הגנטי mk:Генетички код nl:Genetische code ja:コドン no:Genetisk kode nn:Genetisk kode pl:Kod genetyczny pt:Código genético ru:Генетический код sr:Генетски код sv:Genetiska koden vi:Mã di truyền zh:遗传密码